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Tuesday, October 2, 2012

Comprehensive Chromosome Screening - panacea or pipe dream? - Part-1

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Chromosomal screening of human blastocyst using CGH

I have had 19
embryos transferred to my uteurs. Only one of it implanted but it failed to develop
into a healthy infant. This shows that not all embryos produced via IVF are
able to develop into a much desired baby. Many women who have undergone IVF ask
this question frequently 'why didn't my embryo implant?' Although there is no
easy answer for this question scientists are trying hard to decipher this
puzzle. Why don't all embryos develop into a baby? What can be done to improve
the success rate of IVF? Can we achieve 100% success rate in ART? Is there a
way to determine which embryo will develop into a healthy baby? A very recent
technological advancement which appears to be promising in improving IVF
success rate is Comprehensive Chromosome Screening (CCS). It utilizes modern
genetic techniques to find out embryos which are genetically normal. Will such
modern genetic screening techniques take IVF to new heights? Will the success
rate of IVF improve dramatically in the coming years? These are all very
interesting questions and I have a made a review which might answer some of the
above questions atleast partly. My next couple of posts will talk about embryo
aneuploidy, aneuploidy detection techniques and whether it will really make a
difference in the field of ART. This topic might be a bit more scientific and difficult to understand. Please write to me if you want to clarify any doubts.﻿﻿﻿﻿

Not all the embryos which enter the
uterine cavity will implant and develop into a baby. If we are able to pinpoint
which embryo has the potential to develop into healthy infant then the success
rate of an IVFcycle will greatly improve.
This will also pave way for elective single embryo transfer (e-SET) which
in turn will prevent the dangers associated with multiple gestations. The universally accepted truth in
reproductive biology is, younger the women; greater is her ability to conceive
and carry a baby to term. As a women age the quantity and quality (genetic
quality!) of her eggs decline. As a result it becomes difficult for older women
to conceive and even if she conceives many pregnancies are lost in the earlier
stages of gestation. They are also prone to giving birth to babies with genetic abnormalities. The genetic analysis of
fetal remains from spontaneous abortion samples (from younger and older women)
revealed that more than 60% of fetuses stopped developing because of the
presence of chromosomal aberrations (incorrect chomosomal
number or content in the cells). Aneuploidyis the most common genetic
aberration present. Oocytes from older
woman are more prone to develop chromosomal aneuploidies. This knowledge and
the failure of most of the embryos generated via Artificial Reproductive Technology (ART) to
develop into babies (only 19% of transferred embryos were delivered) lead to
the genetic screening of embryos for chromosomal defects. The field which deals
with the screening of embryos for their aneuploidy status is called preimplantation genetic diagnosis (PGD). Until
recently, the widely used screening technique in the field of PGD is called Fluorescence in situ hybridization (FISH).
Preimplantation genetic screening (PGS) using FISH failed to show improvement
in the implantation rates and delivery rate for women of advanced
maternal age. This lack of improvement in pregnancy rate was attributed to the
limitation of FISH technique itself. Using FISH it is only possible to screen a
very limited amount of chromosomes (5-12 chromosomes) for genetic abnormality
or aneuploidy. An anueploidy can strike any of the 24 different chromosomes
present in a human embryo. It is argued that FISH failed to detect embryo
aneuploidy in many of the embryos and as a result there is no improvement in
pregnancy rate of women of advanced maternal age even with PGS. Recently
limitations in FISH technique are overcome by the introduction of genetic
screening techniques which could screen all 23 pairs of chromosomes in human
embryos. This screening technique is called Comprehensive Chromosome Screening (CCS) and it
employs genetic screening techniques like whole genome amplification combined
with qPCR,SNP microarray-based analysis or array-comparitive genomic hybridization (aCGH).

More than 50% of embryosgenerated via IVF are found to carry some forms of aneuploidy. ( This is true of embryos created in the
bedroom as well ! Human reproduction is remarkably inefficient). Even embryos
which appear perfectly normal under the microscope (scored using cell size and
number, presence of multinucleation, percentage of fragmentation and cleavage
rate) are found to carry genetic abnormalities. Surprisingly, an ugly looking
embryo under the microscope can be genetically normal and a beautiful looking
embryo can be genetically abnormal. The high aneuploidy rates found in embryos
might explain the low implantation rate and birth rate per embryo transfer.
Most clinics around the world have a success rate of 40-45% per IVF cycle. This
rate goes down drastically for women over 38 years of age. Advanced maternal
age also leads to high level of spontaneous abortion because of the
implantation of genetically defective embryos which fail to progress normally
in utero .The embryo chromosomal abnormality rate is about 40% for women aged
up to 29 ; and it increases up to 80% for those aged 40 or above. This increase
in genetically defective embryos in older woman is usually due to the increase
in trisomies. More than 50% of aneuploid embryos have the
capacity to develop and implant. Some of these embryos can even develop into
babies , which are genetically abnormal. Aneuploidies that can result in viable
pregnancies include chromosome 13, 18, 21, X and Y. The common genetic
anomalies present in embryos are:

1) Increased implantation rates and live birth rate per embryo transfer and hence encourage the use of elective single embryo transfer (e-SET). This in turn will prevent multiple pregnancies and the risks associated with this.

4) Patients with recurrent implantation failure (RIF) or repeated IVF failure. Patients who have had more than 10 good looking embryos transferred into their uterus without ever achieving a pregnancy are considered as having recurrent implantation failure.

5) For patients who suffer from unexplained infertility. Genetic screening of embryos might help in understanding whether unexplained infertility is embryo related or implantation related.

4 comments:

Very nice and comprehensive post. I'd just add that I've had RPL, with 3 losses, and I know for a fact that 2 out of my 3 losses have been due to aneuplodies. But then, I'm neither of advanced maternal age and both my donor and I have normal karyotypes.

What I'm trying to say is, anybody with RPL should also qualify, even if they have never tested the products of conception for aneuplodies.

Thamks : ) I got the interest to read about CCS after I saw your post. Then thought why not make a short write-up and it ended up very long : )

Jay, if I can ask you-how old are you? Are you using the same donor again? I am not sure whether all women with RPL should do CCS especially when no detectable chromosomal abnormality is present in their conceptus.

You know about me-right? A bit conservative biologist! To tell the truth I am tempted when I first read the very positive CCRM papers-69% implantation rate (with heart tone!), great! But my further read about their publications did not convince me. It is hard to think that it can be a panacea for women like us. I have 5 frozen embies. I will transfer them and see where my journey leads me to. If I get a chance I would love to experiment too but I am wondering whether I could afford such a costly experiment and the emotional turmoil will be high too!

But I am eagerly watching your journey Jay. Lots of good luck! I want to ask you many things but then felt I should not be too inquisitive and so kept quiet.

I am actually very happy to see your comment. Read my other posts on this topic. I would love to have a serious arguement-perhaps it benefits us both! I will be delighted to argue with an intelligent person like you. Correct me too if I am wrong somewhere.

I had turned 30 when I had my first loss, which was chromosomally normal, but hey, they got to read 3 hardy cells of the placenta about an easy 3 weeks after embryonic death. A few months after that, I had my second loss, which was chromosomally abnormal.I had just turned 32 when I conceived my 3rd pregnancy, which was also chromosomally abnormal.

And yes, I'm using the same donor again. The only way he could be contributing if there is some genetic incompatibility between us (such as each of us having one copy of an embryonic lethal recessive mutation or something), but that is a super low odds probability.The higher odds are that the issue is with me.

I think the thing that swung me for PGD was my own experience and also the finding that even with a women using egg donors(such as Brave IVF GIRL) almost 30-40 % of embryos were aneuploid. There are many, many studies that support that is is probably the basal level of aneuploidy in IVF-generated embryos. The question is whether women with infertility have an even higher level of aneuploidy-- if so one saves a lot of time and heartache and money by eliminating the ones that have no chance of succeeding. However, there remains the flip side, the practical difficulties of performing PGD, and the issue of mosaicism. From what I've read I'd agree with Dr. Malpanis conclusions- a blastomere biopsy is no good, the risk-benefit ratio skews heavily in favor of risk.A tropectoderm biopsy, done by capable hands with a good testing platform, skews in favor of benefit, IMO. So at the end of the day, it comes down to practicalities of whether one has the resources to actually test, with minimal damage to the embryos.

I liked your point about aneuploidy being likely confined to cells that form the placenta in the blastocyst and the resulting mislabeling of the embryoas aneuploid. Its a relevant point, but this, IMO represents an acceptable risk, if you have a lot of embryos to test. If you have a very small number of embryos, then of course your best chance is to leave it to mother nature.

Please feel free to ask questions or comment if you see any debatable point on my blog! I'd welcome it, and it would liven things up :)

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Please note that I have no medical training or qualifications, and that the contents of this blog are thereof are opinions, not medical advice.

have medical training or qualifications, and that the contents thereof are opinions, not medical advice. - See more at: http://healthbeat.areavoices.com/2010/09/29/the-expert-patient/#sthash.YPxLA3EA.dpuf

have medical training or qualifications, and that the contents thereof are opinions, not medical advice. - See more at: http://healthbeat.areavoices.com/2010/09/29/the-expert-patient/#sthash.YPxLA3EA.dpufPlease note that I have no medical training or qualifications, and that the contents of this blog are thereof are opinions, not medical advice.

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I am a 36 year old Indian woman, happily married for seven years. This blog captures the 7 year infertility journey we went through to have our daughter Anisha. I have to undergo7 IVF/ICSI cycles, three miscarriage (including a still birth where I lost my twins to incompetent cervix) and 3 FETs to have our little miracle in hand. This journey was excruciatingly painful at times yet shaped me in ways happy times wouldn't have. Looking back, I wonder about myself ! I feel proud that I was able to be sane and strong after so many IVFs and heartbreaking miscarriages. Now I am very happy and serene than if I would have had children without any problems ( a bit crazy too ! :) The secret is, infertility is a great teacher. It taught me to be strong, humble, resilient, rational, forgiving, empathizing and hopeful. BTW, I am a scientist by profession. I hold a doctorate degree in Human Biology and I believe my education has helped me to tackle infertility bravely. I would like to share my experience and knowledge which I gained during this happy struggle to meet our offspring with you all. If you could share with me your thoughts and experiences I will be very happy !